This program project seeks to systematically address crucial questions about the interplay between innate responses to HIV-1 infection. We anticipate to dissect the complete repertoire of cellular sensors and effectors involved in the innate signaling pathways that respond to HIV-1. Moreover, the rate-limiting components and the crosstalk between these pathways will provide critical information about important key players in the response to HIV-1. We also anticipate to acquire a novel understanding of the kinetics of HIV-1 infection regulated by these pathways and the effect of these pathways on the clinical outcome of infection. The systems-level understanding of these processes will be used to construct mathematical models that can predict the behavior of these pathways to HIV-1 infection. These integrated pieces of information about the host-pathogen interface will be invaluable for future optimization of antiviral and vaccine approaches. Scientific projects taking place within the scope of the Program Project will rely to a great extent on largescale production of viruses and siRNA, shRNA and cDNA technologies in high-throughput format as a result of the genomics nature of the approach. The goal of the Molecular Virology and Systems Biology Screening Core is to support the scientists in all aspects ofthe large-scale and system-biology screening approaches by providing state-of-the-art cellular genomics technologies and molecular virology tools. The PI has significant experience in the field of systems-biology. Dr. KOnig will provide her collective expertise in Virology for over 11 years and her experience in developing and employing systems-biology screening tools. These studies are expected to provide global molecular insight into cellular and viral processes that regulate early immune responses to HIV infection.